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PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR

Rosa Bernardi1, Ilhem Guernah, David Jin

  • 1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.

Nature
|August 18, 2006
PubMed

Insights

The promyelocytic leukaemia (PML) protein suppresses new blood vessel formation (neoangiogenesis) by regulating protein synthesis. Loss of PML enhances tumour growth and blood vessel development, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Loss of the promyelocytic leukaemia (PML) tumour suppressor is linked to various human cancers.
  • PML's known functions include inducing growth arrest, cellular senescence, and apoptosis.

Purpose of the Study:

  • To investigate PML's role in neoangiogenesis under both ischemic and neoplastic conditions.
  • To elucidate the molecular mechanisms by which PML regulates new blood vessel formation.

Main Methods:

  • Investigated PML's effect on protein translation, specifically hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis.
  • Examined the interaction between PML, mammalian target of rapamycin (mTOR), and Rheb.
  • Assessed the sensitivity of Pml-/- cells and tumors to rapamycin treatment.
  • Analyzed ribosomal protein S6 phosphorylation and tumour angiogenesis in mouse and human samples.

Main Results:

  • PML acts as a critical inhibitor of neoangiogenesis in vivo.
  • PML represses mTOR activity, thereby controlling HIF-1alpha synthesis under hypoxic conditions.
  • PML physically interacts with mTOR, promoting its nuclear accumulation and negatively regulating its association with Rheb.
  • Pml-/- cells and tumors exhibit increased sensitivity to rapamycin and show elevated angiogenesis and ribosomal protein S6 phosphorylation.

Conclusions:

  • PML is identified as a novel suppressor of mTOR signaling and neoangiogenesis.
  • The findings highlight PML's crucial role in controlling tumour vascularization and growth.

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